SUMMARY - OVERALL PROGRAM Head and neck squamous cell carcinoma (HNSCC) is a worldwide public health problem and cancer patients have limited effective treatment options. For the first time in 50 years, overall survival has been impacted in HNSCC patients with the FDA approval of anti-PD1 monotherapy. However, only a small subset of HNSCC patients derives clinical benefit. The goal of our Program is to build upon the incremental successes of immunotherapy and improve clinical outcomes by addressing the two main barriers to achieving clinical response to immunotherapy: (a) the tumor's overall poor antigenicity (intrinsic mechanism), which limits the generation of antitumor immunity, and (b) innate and adaptive immune suppression (extrinsic mechanism) that results in immune tolerance. The overarching goal of this Program Project (P01) is to gain further insight into both mechanisms of HNSCC immune resistance, so as to overcome them through the rational design and rapid translation of novel combinatorial immunotherapeutic strategies which will eventually increase the number of HNSCC patients who may derive clinical benefit from immunotherapy. To accomplish these goals, the Program seeks to achieve the following overall aims: Overall Aim 1: Uncover both intrinsic and extrinsic mechanisms of immune resistance in HNSCC patients. Overall Aim 2: Develop rationale, novel combinatorial strategies that translate into clinically meaningful responses. These aims leverage innovations in concepts and methodology and are coupled with expertise in head and neck oncology, HLA biology, antigenic peptide discovery, lymphocyte and myeloid cell biology, genomics/epigenomics, antibody drug conjugate therapy, and mouse modeling. The broad aims will be implemented with 3 inter-related and focused Projects and 3 Shared Resource Cores: - Project 1: Therapeutically improving HNSCC antigenicity through epigenetic reprogramming (Dr. Pai) - Project 2: Redirecting pre-existing anti-viral immunity to HNSCCs with APECs (Dr. Cobbold) - Project 3: Myeloid-lymphoid cell crosstalk in HNSCC therapy (Dr. Pittet) - Administrative Core (Drs. Pai/Wirth) - Core 1: Diagnostic Immunopathology and Imaging Core (Drs. Sadow/Faquin) - Core 2: Immune Bioinformatics and Computational Biology Core (Drs. Xavier/Sartor) At the end of the 5 years, we aim to have initiated several clinical trials of combinatorial strategies in head and neck cancer patients, which will be grounded on the data generated from this P01. We expect the overall Program will have a significant impact on the clinical outcomes of head and neck cancer patients and its discoveries also have the potential to impact the larger immuno-oncology field.